The Latest Advances in Peptide Receptor Radionuclide Therapy for Gastroenteropancreatic Neuroendocrine Tumors

PANCREATIC NETS

In the prospective randomized noncomparative phase II study OCLURANDOM (2), patients with somatostatin receptor (SSTR) imaging–positive advanced pancreatic NETs with progressive disease were randomized 1:1 to ¹⁷⁷Lu-DOTATATE, 7.4 GBq every 8 wk for 4 cycles (¹⁷⁷Lu-octreotate arm, n = 41), or the antiangiogenic agent sunitinib, 37.5 mg/d (sunitinib arm, n = 43). Among the included patients, 81% had grade 2 or 3, 37% had a Ki-67 of more than 10%, 42% had more than 25% liver involvement, 43% had received 2 or more prior systemic lines, and 57% had received prior chemotherapy. The primary endpoint was met, with a 12-mo PFS rate of 80% in the ¹⁷⁷Lu-octreotate arm and 42% in the sunitinib arm. Median PFS was 20.7 mo in the ¹⁷⁷Lu-octreotate arm and 11 mo in the sunitinib arm. Grade 3 or higher adverse events occurred less frequently in the ¹⁷⁷Lu-octreotate arm (44%) than in the sunitinib arm (60%). Other important results are expected with final trial analysis.

Some ongoing phase III trials enrolled both pancreatic NET patients and gastroenteric NET patients. COMPETE (NCT03049189) is comparing ¹⁷⁷Lu-DOTATOC with the mammalian-target-of-rapamycin inhibitor everolimus in grade 1 or 2 gastroenteropancreatic NETs, with 309 enrolled patients. Substudies within this trial are investigating the role of dosimetry. NETTER-2 (NCT03972488) and COMPOSE (NCT04919226) are exploring the role of PRRT in gastroenteropancreatic NET patients with high grade 2 or 3 tumors (Ki-67 range, 10%–55%).

SSTR ANTAGONISTS

Somatostatin antagonist analogs are not internalized but display higher occupancy and more prolonged binding to SSTR than do agonists. In a phase I study of ¹⁷⁷Lu-satoreotide tetraxetan (also called ¹⁷⁷Lu-IPN01072, ¹⁷⁷Lu-OPS201, and ¹⁷⁷Lu-DOTA-JR11) in 20 NET patients, the maximum activity was 7.4 GBq/cycle (3). Although response rates were encouraging, 4 of 7 patients (57%) experienced grade 4 hematologic toxicity after cycle 2, hence leading to a modification in the protocol. A phase I/II trial (NCT02592707) with ¹⁷⁷Lu-satoreotide has now completed its recruitment. Part A enrolled 15 patients who received 3 cycles of ¹⁷⁷Lu-satoreotide tetraxetan with 4.5 GBq (peptide mass, 300 μg)/cycle. Part B enrolled 25 patients who completed 1–5 cycles at different administered activities (4.5 or 6.0 GBq/cycle) and peptide masses (300, 700, or 1,300 μg/cycle). Preliminary reporting at the European Society of Medical Oncology 2020 meeting described safety and early efficacy data (4). The major toxicities were hematologic, the objective response rate was 21%, and for the 20 patients with adequate follow-up, the disease control rate at 12 mo was 90%.

¹⁷⁷Lu-DOTA-LM3 is another SSTR antagonist, recently evaluated in 51 metastatic NET patients (5). ⁶⁸Ga-NODAGA-LM3 PET/CT was used for patient selection. Therapy cycles ranged between 1 (half the patients) and 4, with a median of 6.1 GBq/cycle. Partial response was obtained in 36.2%. Grade 3 thrombocytopenia occurred in 5.9% of patients.

α-THERAPY AND OTHER PROMISING RADIONUCLIDES

Initial results with α-emitting radioligands are also promising. A phase 1 dose-escalation trial evaluated ²¹²Pb-DOTAMTATE in PRRT-naïve NET patients (6). In the absence of dose-limiting toxicity, the recommended phase 2 dose was established at the highest activity tested, defined as a 2.50 MBq/kg dose of ²¹²Pb-DOTAMTATE administered 4 times at 8-wk intervals. For the first 10 subjects treated at this recommended activity, the objective response rate was 80%. There were 2 cases of transient renal toxicity and 1 case of renal toxicity that did not recover, but that patient had several confounding factors. A phase II study of ²¹²Pb-DOTAMTATE (NCT05153772) is ongoing.

In a single-center study, 91 patients received ²²⁵Ac-DOTATATE (100–120 kBq/kg of body weight) at 8-wk intervals (median, 4 cycles; range, 1–10). All patients received concomitant capecitabine therapy (7). Fifty-seven had received prior ¹⁷⁷Lu-DOTATATE therapy, with 33 being considered to have progressive disease or disease refractory to ¹⁷⁷Lu-PRRT. Treatment-related toxicities were deemed minimal. Among 79 patients with assessable disease, the objective response rate was 51%. The 24-mo PFS was 67.5%. Prior ¹⁷⁷Lu-PRRT–refractory disease was associated with poorer PFS. A prospective phase 1b/3 trial (NCT05477576) of ²²⁵Ac-DOTATATE in gastroenteropancreatic NET patients who experienced progression after ¹⁷⁷Lu-somatostatin analog therapy is ongoing.

From preclinical studies, the combined β- and Auger-emitter ¹⁶¹Tb also appears promising, especially when coupled to an SSTR antagonist, probably leading to substantial damage to tumor cell membranes (8).

⁶⁷Cu-SARTATE PRRT can be paired with ⁶⁴Cu-SARTATE with the potential for dosimetry planning (9). The chelator MeCOSar (5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid) offers improved retention of copper compared with previous chelators. ⁶⁷Cu-SARTATE has entered clinical trials, albeit in neuroblastoma (NCT04023331).

LIVER-DOMINANT DISEASE

A subtle way to increase the uptake of radioligands in liver metastases could be the use of intraarterial PRRT after selective catheterization of the hepatic artery. A non–head-to-head comparison of intraarterial PRRT (15 patients) versus the standard intravenous route (14 other patients) found that intraarterial PRRT was associated with a higher concentration and absorbed dose in liver metastases (10). Whether a higher response rate was achieved was not reported. Prospective studies are needed since earlier reports were not uniformly positive. Trials with intraarterial ¹⁷⁷Lu-DOTATATE are ongoing (NCT03590119, NCT04837885).

COMBINATION THERAPY

Many studies have investigated PRRT combined with chemotherapy, notably in higher-grade tumors or ¹⁸F-FDG–avid metastatic disease. as it is associated with a poorer prognosis (11). A phase II study evaluated ¹⁷⁷Lu-DOTATATE (5 cycles of 5.5 GBq each) plus oral capecitabine in the intercycle in patients with ¹⁸F-FDG–positive advanced gastroenteropancreatic NETs (12). Of 37 enrolled patients, 68% had G2 or G3 NETs and 68% had pancreatic NETs. Grade 3 or 4 adverse events included hematologic toxicity (16.2%), diarrhea (5.4%), and asthenia (5.4%). Five patients (13%) discontinued the protocol. No renal toxicity was observed. A partial response 3 mo after the end of the 5 cycles was obtained in 10 of 33 evaluable patients (30%). The median PFS was 31.4 mo but still was difficult to interpret in the absence of randomization. The phase II CONTROL NET trial presented at 2022 meeting of the American Society of Clinical Oncology evaluated the combination of PRRT (¹⁷⁷Lu-DOTATATE) and capecitabine plus temozolomide (CAPTEM) in 75 patients with advanced progressive NETs (45 midgut NETs and 27 pancreatic NETs) (13). Patients with midgut NETs were randomized 2 to 1 to PRRT + CAPTEM (n = 33) or PRRT alone (n = 14), and those with pancreatic NETs were randomized 2 to 1 to PRRT + CAPTEM (n = 19) or CAPTEM alone (n = 9). A nonsignificant trend for better PFS (hazard ratio, 0.41; P = 0.08) with PRRT + CAPTEM was observed for pancreatic NET patients, suggesting continuing investigations in this subgroup of NET patients only (13). The risk of long-term hematologic toxicity should be considered (14).

There is also a lot of exciting preclinical work and ongoing trials in NET patients on the combination of PRRT with immune checkpoint inhibitors, such as pembrolizumab (NCT03457948) or nivolumab (NCT04525638), or with DNA-damage response-modifying agents, such as the poly(adenosine diphosphate-ribose) polymerase inhibitors olaparib (NCT04086485, NCT04375267) and talazoparib (NCT05053854), the DNA-dependent protein kinase inhibitor peposertib (NCT04750954), or the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine; Nanoshift, LLC) (NCT04234568).

The mentioned clinical trials, and others investigating the role of dosimetry and predictive imaging and blood biomarkers to improve patient selection and precision medicine approaches to personalized treatment, will no doubt further reinforce the role of PRRT in gastroenteropancreatic NET patients in the years to come.

DISCLOSURE

¹⁷⁷Lu-DOTATATE for the academic OCLURANDOM trial was supplied by AAA/Novartis. Eric Baudin and David Taïeb are advisors for AAA/Novartis. Rodney Hicks is a shareholder of Telix Pharmaceuticals. No other potential conflict of interest relevant to this article was reported.